title: Innate immune response of alveolar macrophage to house dust mite allergen is mediated through TLR2/-4 co-activation.
abstract: House dust mite, Dermatophagoides pteronyssinus (Der p), is one of the major allergens responsible for allergic asthma. However, the putative receptors involved in the signalization of Der p to the innate immune cells are still poorly defined as well as the impact of their activation on the outcome of the allergen-induced cell response. We previously reported that the HDM activation of mouse alveolar macrophages (AM) involves the TLR4/CD14 cell surface receptor complex. Here using a TLR ligand screening essay, we demonstrate that HDM protein extract engages the TLR2, in addition to the TLR4, in engineered TLR-transfected HEK cells but also in the MH-S mouse alveolar macrophage cell line model. Moreover we found that the concomitant recruitment of the MH-S cell's TLR2 and TLR4 receptors by the HDM extract activates the MyD88-dependent signaling pathway and leads to the secretion of the NF-κB regulated pro-inflammatory factors NO and TNF-α. However unlike with the canonical TLR4 ligand (i.e. the bacterial LPS) mobilization of TLR4 by the HDM extract induces a reduced production of the IL-12 pro-inflammatory cytokine and fails to trigger the expression of the T-bet transcription factor. Finally we demonstrated that HDM extract down-regulates LPS induced IL-12 and T-bet expression through a TLR2 dependent mechanism. Therefore, we propose that the simultaneous engagement of the TLR2 and TLR4 receptors by the HDM extract results in a cross regulated original activation pattern of the AM which may contribute to the Th2 polarization of the allergen-induced immune response. The deciphering of these cross-regulation networks is of prime importance to open the way for original therapeutic strategies taking advantage of these receptors and their associated signaling pathways to treat allergic asthma.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France ; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France ; Institutes of Basic Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Chia-Fang
authors.initials: CF
authors.lastname: Liu
authors.forename: Daniel
authors.initials: D
authors.lastname: Drocourt
authors.forename: Germain
authors.initials: G
authors.lastname: Puzo
authors.forename: Jiu-Yao
authors.initials: JY
authors.lastname: Wang
authors.forename: Michel
authors.initials: M
authors.lastname: Riviere
mesh_terms: D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000096:biosynthesis; D008024:Ligands; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000098815:T-bet Transcription Factor
chemical_list: D039741:Antigens, Dermatophagoides; D008024:Ligands; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide